This proposal requests funds for the purchase of a new tandem time-of- flight/time-of-flight mass spectrometer with MALDI ionization (MALDI- TOF/TOF). This shared instrument will be used for structural studies of bio-macromolecules and their myriad covalent modifications that are of critical importance to ongoing research in the biological and medical sciences in the San Francisco Bay Area. It will be housed in the NIH NCRR-supported Mass Spectrometry Resource at UCSF. This environment ensures the availability of the scientific, technical and management expertise required to optimize its productivity in solving problems at the forefront of macromolecular biology and medicine for a large number of investigators. The proposed instrumentation will provide previously unavailable absolute sensitivity combined with high resolution and high mass accuracy for-high energy CID sequencing of biomolecules such as peptides, glycopeptides and oligosaccharides to project investigators with established needs. This proposal describes 16 projects for major users who are a group of more than 20 scientists and clinicians involved in over 50 NIH-supported research programs. These research projects are at the forefront of biomedical problems concerning the identification of native and covalently modified peptides, proteins carbohydrates and nucleic acids required in deciphering cell function and dysfunction. All of these studies require the highest possible sensitivity of detection and will benefit greatly from other aspects of the outstanding performance of the instrument requested. Dr. Charles Craik, Professor of Pharmaceutical Chemistry, Pharmacology and Biochemistry and Molecular Biology will chair the Advisory Committee responsible for the overall guidance of the shared instrument's use. The committee will assure that the time is shared equitably and that some 15% of its time will be made available to other projects requiring its unique capability. Mr. David Maltby, who has extensive experience in electrospray and other types of biological mass spectrometry, will oversee scheduling, training and maintenance and will provide daily supervision of usage. Long term productive usage and maintenance will be assured by the close association with a major Mass Spectrometry Facility and financial support of the major users.